A number of factors have been implicated in initiating and sustaining alcohol abuse and alcoholism. Critical among these factors are, adolescent alcohol exposure, which increased the risk of adult alcoholism, and stress, which is a primary factor in relapse. In animal models, repeated stresses prior to one-week exposure to ethanol and withdrawal (Stress/WD protocol) sensitized rats to withdrawal-induced anxiety, another factor implicated in alcoholism. Stress has also been documented to increase cytokines in the brains of adolescent and adult rats. Accordingly, preliminary research revealed that substituting lipopolysaccharide (LPS), a substance known to induce cytokines, for the initial stresses in the Stress/WD protocol increases cytokines in brain and sensitizes withdrawal-induced anxiety. Furthermore, there was a concomitant increase in 14-GABAA receptor subunits 3 days after withdrawal following the LPS/WD protocol. Preliminary efforts have concluded that cytokines contribute to and/or substitute for the action of stress in enhancing maladaptive changes induced by ethanol that leads to increased withdrawal-induced anxiety and 14 subunit changes in the cortex-a potential mechanism linking adolescent drinking and adult alcoholism. Therefore, subsequent efforts will focus on characterizing the time course of changes in GABAA receptor expression within specific areas throughout the brain in response to the LPS/WD protocol. To assess if this adaptive change has regional specificity, these assessments will be made in other regions of brain including the cortex, hippocampus, and amygdala. Furthermore, GABAA receptor function will be assessed with electrophysiological studies to test changes in synaptic and extrasynaptic GABA function following LPS/WD protocol. Overall, this work tests the hypothesis that the LPS/WD protocol induces persistent adaptation in GABAA receptor function in the adolescent brain that regulates sensitization of withdrawal-induced anxiety previously established by the protocol. These experiments will lay the foundation for understanding the role of cytokines in contributing to the functional pathology that increases risk of alcoholism in adulthood after adolescent alcohol exposure. PUBLIC HEALTH RELEVANCE: Adolescent exposure to alcohol is an ever more prevalent occurrence. As many as 80% of high school students have reported trying alcohol by the time they graduate. These numbers are alarming considering the increased risk of adult alcoholism following adolescent drinking. Changes in GABAA receptor function may mark persistent changes in neuronal function that lead to this increased risk. Through efforts to better define changes in neuromechanisms following early exposure to alcohol, we can begin to develop strategies to prevent and reverse lasting consequences of adolescent exposure.